Ribosomes are molecular machines that carry out an essential biological task: they synthesize proteins. Thus, bacterial ribosomes are logical targets for antibiotics. However, the emergence (and growth of) drug resistant bacteria poses a major threat to human health. New strategies for attacking resistant strains must be developed. Recent, breakthrough structural studies of the ribosome enable an entirely new approach to interfering with the ribosome: preventing its self assembly. Here, we propose to develop and apply a new experimental method for measuring structural changes accompanying the real time self-assembly of the ribosome or its subunits. If successful, this approach will enable identification of folding pathways or partially folded states that may be amenable to attack. PUBLIC HEALTH RELEVANCE: Large molecular machines, like the ribosome, are constructed from both RNA and protein precursors. The methods we propose will provide unique insight into self-assembly of large ribonucleoprotein complexes, like the ribosome. A long term goal of this work is to guide development of a new generation of antibiotics that interfere with self-assembly. If the approach is successful, this knowledge brings an additional weapon to the fight against antibiotic resistant bacteria, an escalating threat to human health.